Weight regain after weight loss continues to be one of the biggest obstacles to treating obesity. Weight reduction leads to strong metabolic adaptations that promote rapid and efficient regain. The objectives of this work are to identify comprehensive therapeutic strategies that will counter these metabolic pressures in order to facilitate long-term weight reduction. Studying these pressures in humans is challenging because of the difficulty in controlling genetic, environmental, and behavioral influences on energy homeostasis. We have developed an experimental paradigm that closely models human regain, provides better control of these other factors, and has well-defined outcomes that specifically describe the metabolic pressures. This paradigm will be employed to characterize the efficacy of two nutritional approaches to weight management and to study a controversial issue related to fuel utilization during the relapse process. In the first specific aim, we propose to examine a low carbohydrate, high protein (LC-HP) diet and a diet high in resistant starch (RS) fiber for their ability to attenuate the metabolic propensity to regain weight after prolonged weight reduction. Because regular exercise is more commonly prescribed than implemented, these strategies will be tested to see if they are effective without exercise, require exercise to be beneficial, or have no effect regardless of the level of physical activity. In the second aim of this proposal, we propose to examine the utilization of ingested fats during the early stages of relapse to assess whether excess calories and compensatory adjustments in peripheral tissues divert ingested lipids away from oxidation and toward storage in adipose tissue. This alternative to the controversial "glucose redistribution hypothesis" may provide a better description the changes in fuel utilization that facilitate rapid and efficient weight regain early in the process of relapse. The first aim will provide practical information about how two nutritional strategies, with or without exercise, affect the metabolic drive to regain weight, and the second aim will provide mechanistic insight into a controversial aspect of the weight regain process. Relevance to Public Health Overcoming the metabolic propensity to regain weight may be the most critical consideration in our fight to control the obesity epidemic. This work will provide valuable information regarding the process of weight regain and the ability of nutritional strategies to alter the metabolic drive to regain weight. These studies may provide important evidence on which to base strategies that will facilitate sustained weight reduction in obese individuals.